The p53 gene controls cell fate and is mutated in at least 50% of all human cancers. The mutations commonly abolish the ability of p53 to bind to DNA as a transcription factor and regulate genes controlling the cell cycle. The loss of p53 function most frequently occurs through random somatic mutations in the TP53 gene, resulting in more than 50% of all human tumors harboring inactivating mutations.
Unlike other tumor suppressor genes which generally undergo deletion mutation during carcinogenesis, approximately 75% of inactivating mutations in TP53 occur due to single base pair missense substitutions, resulting in the synthesis of a stable full-length mutant protein with defective wild-type gene transactivation functions. Other genetic alterations which occur at much lower frequencies include frameshift insertions and deletions, nonsense mutations and silent mutations. Critical amino acid mutations arising from nucleotide substitutions at highly mutable CpG dinucleotides account for 30% of all missense mutations. Missense mutations of the TP53 gene has been detected anywhere within the coding region but tend to cluster within the DNA binding core domain of the protein (>95%), with 6 specific residues being identified as mutational hotspots' in human cancer (R175, G245, R248, G249, R273 and R282). Given that more than 50% of all human tumors harbor inactivating mutations in the TP53 gene, there has been interest in reactivating mutant p53.
Several peptides and compounds have been described which can interact with certain p53 mutants to restore some essential transactivation. However, the efficacy of these tends to be suboptimal and/or they are toxic to cells.
There is therefore a need to provide an alternative peptide capable of reactivating mutant p53 that overcomes or at least ameliorates one or more of the disadvantages above.